Enantiomeric specificity of (-)-2,2',3,3',6,6'-hexachlorobiphenyl toward ryanodine receptor types 1 and 2.
Polychlorinated biphenyls (PCBs) with unsymmetrical chlorine substitutions and multiple orthosubstitutions that restrict rotation around the biphenyl bond may exist in two stable enantiomeric forms.Stereospecific binding and functional modification of specific biological signaling targets have not been previously described for PCB atropisomers. We report that (-)-2,2',3,3',6,6'-hexachlorobiphenyl [(-)-PCB 136] enhances the binding of [3H]ryanodine to high-affinity sites on ryanodine receptors type 1(RyR1) and type 2 (RyR2) (EC50 values ~0.95 microM), whereas (+)-PCB 136 is inactive at < or =10 microM.(-)-PCB 136 induces a rapid release of Ca2+ from microsomal vesicles by selective sensitization of RyRs, an effect not antagonized by (+)-PCB 136. (-)-PCB 136 (500nM) enhances the activity of reconstituted RyR1 channels 3-fold by stabilizing the open and destabilizing the closed conformational states. The enantiomeric specificity is also demonstrated in intact HEK 293 cells expressing RyR1 where exposure to (-)-PCB 136 (100 nM; 12 h) sensitizes responses to caffeine, whereas (+)-PCB 136 does not. These data show enantiomeric specificity of (-)-PCB 136 toward a broadly expressed family of microsomal Ca2+ channels that may extend to other chiral noncoplanar PCBs and related structures.Evidence for enantioselective enrichment of PCBs in biological tissues that express RyR1 and RyR2channels may provide new mechanistic leads about their toxicological impacts on human health
Pessah
Isaac N
IN
Department of VM, Molecular Biosciences and UC Davis Center for Children's Environmental Health, University of California, One Shields Avenue, Davis, California 95616, USA. inpessah@ucdavis.edu
Lehmler
Hans-Joachim
HJ
Robertson
Larry W
LW
Perez
Claudio F
CF
Cabrales
Elaine
E
Bose
Diptiman D
DD
Feng
Wei
W
D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000633:toxicity; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013237:Stereoisomerism
D019837:Ryanodine Receptor Calcium Release Channel; D011078:Polychlorinated Biphenyls; C010498:2,3,6,2',3',6'-hexachlorobiphenyl